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NIH Awards Nearly $2M to Fund Research into RNA Delivery, Argonaute 2

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The National Institutes of Health this month set aside roughly $1.4 million to fund three grants exploring different microRNA- and siRNA-delivery approaches. The agency also awarded more than $350,000 to support research into how the structure of Argonaute 2 impacts its role in RNA silencing.

The first grant was awarded to University of Louisville researcher Huang-Ge Zhang, who is developing naturally derived exosome-like nanoparticles for the delivery of miRNAs and other extracellular RNAs.

This month, Zhang and colleagues reported on the selective uptake of orally administered grapefruit-derived nanovesicles by intestinal macrophages. Notably, the team incorporated an anti-inflammatory small molecule drug into the nanovesicles and demonstrated a therapeutic effect in a mouse model of colitis. And earlier this year, the researchers published a report showing that nanoparticles composed of grapefruit-derived lipids can be used to deliver siRNAs into different cell types.

In his grant’s abstract, Zhang noted that a limitation facing the use of such fruit-derived delivery vehicles in a clinical setting is the need for large-scale production. However, preliminary data from his group indicates that exosome-like nanoparticles can be isolated in large quantities from the tissue of edible plants, including grapes.

Such edible plant-derived nanovectors, or EPNV, can be assembled from grape exosome-like derived lipids and are capable of encapsulating siRNAs, he wrote. These particles can also be targeted to specific tissues in a variety of ways.

For instance, their co-delivery with folic acid results in preferential delivery to tumor tissue, while their reduction in size via pore size filters “significantly enhances … translocation to the brain.” Oral delivery, meantime, results in migration to the liver.

Based on these and other data, and with the support of the NIH, Zhang aims to test whether orally administered EPNVs can deliver a specific miRNA — miR-17 — to metastatic colon tumor cells in the liver. Given that natural killer cells express the miRNA, the compound is expected to kill the tumor cells.

He also plans to test whether EPNV-encapsulated miR-155 — a miRNA linked to tumor suppression — promotes “differentiation of myeloid derived suppressor cells into mature dendritic cells in mouse breast/brain tumor models,” according to the abstract.

Finally, he and his lab will explore whether the miRNA/EPNV formulations trigger side effects in mouse tumor models, and whether such compounds can be economically produced on a large scale.

The two-year grant began on Aug. 1, and is worth $398,220 in its first year.

The second grant went to Ohio State University’s Thomas Schmittgen to support his research into the tumor-targeted delivery of miRNA-loaded microvesicles.

Schmittgen has long studied the role of miRNAs on cancer, and in 2010 reported that miR-199a-3p is decreased in hepatocellular carcinoma and that its expression could kill CD44-positive liver cancer cells.

Building off these findings, he and his colleagues plan to use the NIH funding to develop microvesicles that produce a targeting peptide directed toward hepatocellular cancer cells and are loaded with pre-miR-199a, he wrote in his grant’s abstract.

“This project will use in silico and biochemical approaches to determine the optimal pre-miRNA sequences for peptide binding, correct processing, and biological activity,” the grant states. “The therapeutic activity and targeting ability of the microvesicle delivery system will be evaluated in vitro and in an orthotopic model of hepatocellular carcinoma. Pharmacodynamic and pharmacokinetic evaluations will provide detailed knowledge on dose, toxicity, efficacy, route of administration, and biodistribution.”

The grant began on Aug. 1 and runs until July 31, 2016. It is worth $499,999 in the first year.

The last delivery-related grant was awarded to Neil Aronin of the University of Massachusetts Medical School for his efforts to develop exosome-based siRNA delivery vehicles for the treatment of Huntington’s disease.

The primary target for disease treatment is the mutant form of the gene huntingtin, which produces a protein found to aggregate in the brains of Huntington’s disease patients. While the gene can be knocked down in mouse models using siRNAs or shRNAs, delivery remains a key hurdle for the approach in humans.

In non-human primates, huntingtin-targeted antisense oligos administered to spinal fluid do not reach the striatum, and the spread of siRNAs delivered this way is “limited in brain,” Aronin noted in the grant’s abstract. Meanwhile, adeno-associated viral vector-delivered shRNAs require several injections into the brain.

To overcome this problem, Aronin and his team have turned to exosomes, noting that such microvesicles with rabies virus glycoprotein, or RVG, on their surface can be injected into the bloodstream, cross the blood brain barrier, and enter neurons and glia. They can also be designed to carry siRNA payloads, which are deposited into neurons and trigger an RNAi effect.

With the support of the NIH grant, Aronin plans to study the ability of these RVG-decorated exosomes to carrying huntingtin-targeting siRNAs across the blood brain barrier and into neurons.

“Localization in brain and RNAi dependent knockdown will be studied,” he noted, and “hyper-functional siRNAs will be sought.”

He and his colleagues will also examine immune reactivity and immune system neutralization since exosomes have potential antigens and a Huntington’s disease therapy would require frequent dosing.

The grant started on Aug. 1 and runs for three years. It is worth $500,000 in the first year.

Back to Basics

Also picking up NIH funding this month was Ian MacRae, a Scripps Research Institute investigator focused on the mechanics of RNAi, for his efforts to develop a structural understanding of Ago2.

Specifically, MacRae is focusing on three key interactions of the protein in the RNA silencing process: guide RNA binding; target RNA recognition; and the binding of the necessary accessory factor TNRC6.

With the structure of Ago2 already determined, he and his team will use different structural and biochemical approaches to try to identify how Ago2 binds guide RNAs and positions them to efficiently identify target RNAs — work that is expected to provide “structural insights for the rational design of improved siRNAs,” according to the grant’s abstract.

“A similar approach will be taken to understand the mechanism by which Ago2 recognizes target RNAs” in order to provide a basis for the “empirical miRNA targeting rules developed by other labs and open new avenues for manipulating these RNAs for both research and therapeutic purposes,” the abstract adds. Determining the structural basis for the association of Ago2 with TNRC6, meanwhile, will help “define the general principles that guide the assembly of the massive complexes required for RNA silencing in vivo

MacRae’s grant runs from Aug. 1 until May 31, 2017, and is worth $360,050 the first year.

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